(12) UK Patent Application (19) GB (11) 2 392 670 (13) A

(43) Date of A Publication

10.03.2004

(21) Application No: 0220385.9
(22) Date of Filing: 03.09.2002
(71) Applicant(s):
Stylacats Limited
(Incorporated in the United Kingdom)
Cheshire Manufacturing Park,
Oil Sites Road, EllESMERE PORT,
Cheshire, CH65 4HF, United Kingdom
(72) Inventor(s):
John Whittall
Paul Mather
(74) Agent and/or Address for Service:
W P Thompson & Co
Coopers Building, Church Street,
LIVERPOOL, l1 3AB, United Kingdom
(54) Abstract Title: (+)-Morphine production (58) Field of Search:

Other: Online:WPI,EPODOC,JAPIO,CAS ONLINE

(51) INT Cl7:

C07D 489/02, A61K 31/485, A61P 25/04

(52) UK CL (Edition W):

C2C CAA CAB U1S S2417

(56) Documents Cited:

US 4025520 A

(57) The invention relates to a process for the production of (+)-morphine from (-)-sinomenine comprising contacting (-)-sinomenine with H2/Pd/C under conditions effective for converting sinomenine to 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof; contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+)-dihydrocodeinone; contacting the resulting (+)-dihydrocodeinone with (MeO)3CH followed by TsOH followed by NBA/MeOH under conditions effective for converting (+)-dihydrocodeinone to novel 1,7-dibromodihydrocodeinone dimethylketal, which is useful against pain contacting the resulting 1,7-dibromodihydrocodeinone dimethylketal with t-butoxide followed by acid under conditions effective for converting 1 ,7-dibromodihydrocodeinone dimethyl ketal to (+)-1-bromocodeinone; contacting the resulting (+)-1-bromocodeinone with LiA1 H4 followed by BBr3 under conditions effective for converting 1 ,7-dibromodihydrocodeinone dimethyl ketal to (+)-morphine; and recovering the resulting (+)-morphine as product.

Printed on Recycled Paper

j

2392670

(

- 1 - DESCRIPTION COMPOUND AND PROCESS

The present invention relates to novel intermediate compounds in a process for the production of (+ )-morphine from (- )-sinomenine and to the production of the novel intermediate compounds and (- )-sinomenine and to certain intermediate steps in such a process.

The function of naturally occurring, (-)-morphine in pain relief is well known. However, recently the properties of its synthetic stereoisomer (+)-morphine have been considered. Stringer et ai, in Neuroscience Letters 295 (2000) 21-24, report that (+)-morphine, but not (-)-morphine, has low micro-molar affinity for the site of the N-methyl-D-aspartate (NMDA) receptor in the rat forebrain and suggest the clinical potential for racemic (+)(-)morphine in the treatment of neuropathic pain.

Although the clinical potential of (+ )-morphine has been postulated, further studies in this area are hindered by the limited commercial availability of (+ )-morphine, a problem highlighted in DDT Vol. 6, No. 14 July 2001 in a review article which goes on to suggest (at p746) alternative approaches to achieving NMDA receptor antagonist activity.

The conversion of (- )sinomenine to (+ )-morphine has been reported by Iijima et al in 1. Org. Chem., Vol. 43, No.7, 1978, p1462, with reference to earlier work by Goto and

(

- 2 -

Yamamoto, Proc. Jpn. Acad., 30, 769 (1954),33,477 (1957) and 34, 60 (1958) and by WellerandRapoportinJ.Med. Chem., 19, 1171 (1976).

It is an object of the present invention to provide an improved synthetic route from (-)sinomenine to (+ )-morphine and to provide novel intermediate compounds which may be useful for production of a medicament for use in the treatment or prophylaxis of pain.

According to the present invention, there is provided a compound of the formula:

Br

or derivative thereof. The compound may be used as an active ingredient in a pharmaceutical preparation. Preferably, the compound or a pharmaceutically active salt thereof may be used in the manufacture of a medicament. The compound or a pharmaceutically active salt thereof, may be used in the manufacture of a medicament for use in the treatment or prophylaxis of pain. It will apparent to those skilled in the art that the medicament may be prepared in a number of formats to allow for different methods of administration, such as oral, intravenous, trans-dermal and suppository for example. It

(

- 3 -

will further be apparent that the medicament may be prepared in a certain manner in order to confer desirable pharmacokinetic or bioavailability properties such as slow release for example.

In accordance with another aspect of the present invention there is provided a process for the production of (+)-morphine (formula 6) from (-)-sinomenine (formula 1) comprising at least two reaction steps and at least one intermediate product, the at least one intermediate product comprising 1,7-dibromodihydrocodeinone dimethylketal (formula 4).

The chemical formulae 1 to 6 referred to herein are specified in the reaction scheme below.

In one process according to the invention, at least three reaction steps and at least two intermediate products are provided, one of the at least two intermediate products comprising 7(S)-(+)-dihydrosinomenine (formula 2) or 7(R)-(+)-dihydrosinomenine or a mixture of both isoforms.

In another process according to the invention, at least four reaction steps and at least three intermediate products are provided, one of the at least three intermediate products comprising (+)-dihydrocodeinone (formula 3).

(

- 4-

In still another process according to the invention, at least five reaction steps and at least four intermediate products are provided, one of the at least four intermediate products comprising (+ )-l-bromocodeinone (formula 5).

In one preferred process according to the invention, (- )-sinomenine is converted to (+)morphine according to the following reaction scheme:

(4) (3)
MeO
Br
! Step 4
MeO HO (

OMe

- 5 -

Step 1

(2)

OMe

Step 3

Step 5

(5)

(6)

(

- 6-

The Preferred reagent for step 1 is H2/Pd/C.

Preferred reagents for step 2 include polyphosphoric acid and Eatons reagent.

Preferred reagents for step 3 include (MeOhcH followed by TsOH or camphorsulphonic acid followed by NBAiMeOH or N-bromosuccinimide (NBS).

Preferred reagents for step 4 include tBuOK followed by H+ .

Preferred reagents for step 5 include LiAIH. followed by BBr3, BCh or trimethylsilyl iodide (TMS-I).

One preferred process according to the invention provides a synthesis of(+)-morphine comprising:

a) contacting (-)-sinomenine with H2/Pd/C under conditions effective for converting (- )-sinomenine to 7(S)-( + )-dihydrosinomenine or 7 (R)-( + )-dihydrosinomenine;

b) contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)dihydrosinomenine or mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-(+)-dihydrosinomenine or 7(R)-

(+ )-dihydrosinomenine to (+ )-dihydrocodeinone;

(

- 7 -

c) contacting the resulting (+ )-dihydrocodeinone with (MeO)3CH followed by TsOH followed by NBAiMeOH under conditions effective for converting (+)dihydrocodeinone to 1,7-dibromodihydrocodeinone dimethylketal;

d) contacting the resulting 1 ,7-dibromodihydrocodeinone dimethyl ketal with tbutoxide followed by acid under conditions effective for converting 1,7- dibromodihydrocodeinone dimethyl ketal to (+)-l-bromocodeinone;

e) contacting the resulting (+)-l-bromocodeinone with LiAlH4 followed by BBr3 under conditions effective for converting (+ )-l-bromocodeinone to (+ )-morphine; and

f) recovering the resulting (+ )-morphine as product.

g) further processing the (+ )-morphine into a medicament.

The invention further provides a process for the synthesis of 1,7- dibromdihydrocodeinone dimethylketal from (-)-sinomenine by steps a) to c) indicated above.

Also provided in accordance with the invention is a process for the synthesis of (+)morphine from 1,7 -dibromdihydrocodeinone dimethylketal by steps d) to f) indicated above.

\

The invention also provides for the (+)-morphine produced by steps a) to t) to be further processed into a medicament. It will be apparent that the medicament may be prepared in a number of formats to allow for different methods of administration and the medicament

(

- 8 -

may also be prepared in a certain manner in order to confer desirable phannacokinetic or bioavailability properties.

The process of the invention will now be more particularly described with reference to the following Example.

Example

A synthesis of (+ )-morphine was conducted in accordance with the invention, using the following process steps.

Step 1- Preparation ofa mixture of7(R)- and 7(S)-(+)-dihydrosinomenine

25g of (-)-sinomenine.HCI was dissolved in 750g methanol. O.5g PdlC was then added. The mixture was then hydrogenated (latm, balloon) with stirring overnight (20hrs). Thin layer chromatography (4: 1 CHCh:MeOH, run up the plate twice) showed the reaction to be complete. The solution was then filtered through Celite and evaporated to dryness to obtain 23.1g of product. Two further reactions on the same scale have produced 24.5g of product.

Step 2(i) - Preparation of (+)-dihydrocodeinone from a mixture of7(R) and 7(S)-(+)dihydrosinomenine

(

\

- 9 -

Polyphosphoric acid (300g) was added to lSg of the mixture of 7(R) and 7(S)-( +)dihydrosinomenine obtained from step 1. The mixture was heated to 70°C and stirred for 1.2Sh. After cooling to room temperature the mixture was poured into a stirred solution of 33% NH3 (200ml), CHCh (200ml) and ice, the addition was slow in order to avoid overheating. Occasionally, more ice was added to control the temperature and fmally NH3 solution was added to make the solution basic (ca pH 8). The solution was then saturated with NaCl and extracted with CHCh (3 x 200ml). The combined extracts were then dried (Na2S04), filtered and evaporated to dryness to provide 7.Sg of product as a beige solid.

Step 2(ii) - Alternative preparation of(+)-dihydrocodeinone from a mixture of7 (R) and 7(S)-( + )-dihydrosinomenine

In an alternative method for Step 2, polyphosphoric acid was replaced with Eatons reagent (7% phosphorus pentoxide in methanesulphonic acid). The reaction was complete after 1000ns at 70°C, affording the product in near quantitative yield as beige solid.

Step 3a - Preparation of (+ )-dihydrocodeinone dimethylketal from (+ )-dihydrocodeinone

(Method derived from that described in J Med Chem, 1976, vol 19, No 10, pJJ 74.) 4.Sg of (+ )-dihydrocodeinone from step 2 was heated with 7.2rnl trimethylorthoformate (TMO) to effect solution. l.4rnl conc. H2S04 was added and the mixture heated to reflux

(

- 10-

(70°). After 6h a small amount of starting material remained and the mixture was left to stir overnight at room temp (17h). Further portions ofTMO (2.5ml) and H2S04 (0.3ml) were added and the solution heated to reflux again for 2h, after which de showed only a trace of the starting material. The cooled mixture was poured into O.SM Na2C03 solution (IOOml) and extracted with CHCh (100ml). The separated organic phase was washed with brine, dried (Na2S04) and evaporated to yield S.lg of product.

Step 3b - Preparation of !l. 6 -dihydrothebaine from (+ )-dihydrocodeinone dimethyl ketal

(Method derived from that described in J Med Chern, 1976, vol 19, No 10, pJJ 74.) A solution ofp-toluenesulphonic acid (2.45g) in dry CHCI) (lOOml) was added to 4.1g of (+)-dihydrocodeinone dimethyl ketal in dry CHCh (IOOml) and the solution then heated at 120°C for 15mins, collecting a distillate of ca 100ml. The reaction mixture was cooled to O°C and poured into cold O.SM Na2C03 (IOOml). The layers were separated and the aqueous phase washed with CHCh (100ml). The combined organic phases were then washed with brine, dried (Na2S04) and evaporated to give 3.5g of desired enol ether as an oil which solidified on standing.

Step 3c - Preparation of 1,7 -dibromodihydrocodeinone dimethylketal

2.1 g of the product enol ether from step 3b was dissolved in CHCh (200ml) and cooled to -SoC. HBr-H20 (1.13ml of a 6.7mrnol solution) was added and the mixture stirred for 2mins. 150m1 of saturated NaBr solution was added (at O°C) and the mixture shaken.

(

- 11 -

The layers were separated and the aqueous phase was washed with 50ml CHCh. The combined organic phases were dried (Na2S04) and evaporated. The residue was then dissolved in methanol (80ml), cooled (to O°C) and treated dropwise with a cooled solution (O°C) ofNBA in MeOH over 30mins. The slightly orange solution was evaporated and dissolved by shaking with CHCh (I50m1) and 2M aqueous NaOH (3Oml). After separation, the aqueous phase was extracted with CHCh (30m1) and the combined organic phases washed with water (1 OOml) and brine (1 OOml) then dried (Na2S04) and evaporated to give 2.5g of a mixture of two compounds by tlc. The major compound was the desired dibrominated product and the minor component was the corresponding monobrominated compound, with the Br occupying the l-position on the dihydrocodeinone ring system, as reported by Weller and Rapoport inJ Med Chern, 1976, vol 19, No 10, pJ174.

Step 4a - Preparation of l-bromocodeinone dimethylketal

The crude product mixture from step 3b was dissolved in 50ml DMSO together with 1.32g potassium tert-butoxide and the mixture stirred overnight at room temperature. A further portion of potassium tert-butoxide O.33g was added and the mixture then heated at 60°C for 6h. After cooling, toluene (150ml) and water (150ml) were added, the layers separated and the aqueous further extracted with toluene (50ml). The combined organics were washed with water (10OmI) and brine (100ml) then dried (Na2S04) and evaporated to give I.S5g of crude product.

(

- 12-

Step 4b - Preparation of (+)-l-bromocodeinone

The bromoketal product from step 4a was dissolved in dilute aqueous HCl and heated at 70°C for 30rnins. On cooling to O°C the solution was neutralised to pH 7 with 2M NaOH (O°C) and then extracted with CHCh (100rnl and 50m1). The combined organic phases were washed with brine and dried (Na2S04). Evaporation afforded an off-white solid (1.15g). The aqueous phase was basified (PH 10) and further extracted with CHCh to afford more product (0.6g). The two product samples gave similar tic results and were combined. Flash chromatography revealed the presence of two compounds in the combined sample, 1-bromocodeinone and l-bromodihydrocodeinone,

Step 5a - Preparation of (+)-codeine

(Method derived from White et ai, Tetrahedron, 1983, 39, 2393, which describes the preparation of (- )-codeine.) Product l-bromocodeinone (40Omg) from step 4b was taken in 20ml THF and 0.2g LiAI~ was added. The mixture was heated under reflux for 14h. After cooling, 1:1 THF:H20 (10ml) was added, followed by saturated aqueous potassium carbonate (5ml). Alternatively, sodium potassium tartrate may be substituted for saturated aqueous potassium carbonate. The mixture was extracted with CH2Ch (100rnl + 50ml) and the combined organic phases were washed with water (100ml) and dried (MgS04). Flash chromatography of the residue afforded (+)-codeine (240mg) as a white solid.

(

- 13 -

Step 5b(i) - Conversion of (+)-codeine to (+)-morphine

(+)-codeine (12Omg) from step Sa was dissolved in CHCh (dry, 2.5m1) and the resulting solution treated under N2 at 20°C with BBr3 solution (2.4m1 of a 1.OM solution in CH2Ch), which was added over two minutes. Stirring was continued for 15mins and the mixture was then poured into a mixture of ice (lOg) and NH40H (28% NH3). Crystalline material formed initially but after 30mins at O°C, the material dissolved. The aqueous mixture was transferred to a separating funnel (rinsing with 10m1 CHCh, 10m1 H20 and 2.Sm1 N&OH), saturated with NaCI and extracted with 3:1 CHCh:EtOH (2 x 2Sm1).

The combined organic phases were dried (MgS04) and evaporated to give l30mg of crude product.

Step Sb(ii) - Alternative conversion of (+)-codeine to (+)-morphine

(+)-codeine (7Omg) from step Sa was dissolved in CHCh (1.5m1) and the resulting solution treated under N2 at room temperature with BBr3 solution (O.94m1 of a 1.OM solution in CH2Ch), which was added over two minutes. Stirring was continued for 15mins and the mixture was then poured into a mixture of ice (8g) and NfI40H (2m1) and stirred for 30mins. Crystalline material formed initially but after 30mins at O°C, the material dissolved. The lower organic layer had the appearance of an emulsion and was separated. However, tic revealed the presence only of impurities. The aqueous mixture was extracted with 3: 1 CHCh:EtOH (2 x 20ml). The combined organic phases were dried (MgS04) and evaporated to give 60mg of crude product.

(

- 14-

The combined crude products from steps 5b(i) and 5b(ii) were dissolved in a minimum volume of methanol and triturated with distilled water. After standing for I5h (+)morphine was afforded as an ofT-white solid.

(

- 15 -

CLAIMS

1. A compound of the formula:

MeO

. '- .

-NMe

Br

(formula 4) or derivative thereof.

2. A pharmaceutical preparation comprising, as an active ingredient, a compound

according to claim 1.

3. A compound according to claim 1 or a pharmaceutically active salt thereof, for use in

the manufacture of a medicament.

4. A compound according to claim 1 or a pharmaceutically active salt thereof, for the

use in the manufacture of a medicament for use in the treatment or prophylaxis of

pain.

5. A process for the production of a compound according to claim 1 wherein (+)-

dihydrocodeinone is treated with (MeO)3CH followed by TsOH followed by

NBAiMeOH under conditions effective for converting (+ )-dihydrocodeinone to 1,7-

dibromodih ydrocodeinone dimethyl ketal.

(

- 16 -

6. A process according to claim 5 wherein the wherein (+)-dihydrocodeinone is produced by treating 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof is with polyphosphoric acid or Batons reagent under conditions effective for converting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+ )-dihydrocodeinone.

7. A process according to claim 6 wherein the 7(S)-(+)-dihydrosinomenine or 7(R)-(+)dihydrosinomenine or a mixture thereof is produced by contacting ( - )-sinomenine with HzIPdlC under conditions effective for converting (- )-sinomenine to 7(S)-( +)dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof.

8. A process according to claims 5 to 7 comprising at least two reaction steps and at least one intermediate product, the at least one intermediate product comprising 7(S)(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof.

9. A process according to claims 5 to 7 for the production of a compound according to claim I comprising at least two reaction steps providing at least one intermediate product, the intermediate products comprising (+ )-dihydrocodeinone.

1 O. A process according to anyone of claims 5 to 9 comprising contacting ( - j-sinomenine with HzIPdlC under conditions effective for converting (-)-sinomenine to 7(S)-(+)dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof; contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof with polyphosphoric acid or Batons reagent under conditions effective for converting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+)-dihydrocodeinone; contacting the resulting (+)-dihydrocodeinone with

- 17 -

(MeO)3CH followed by TsOR followed by NBNMeOH under conditions effective for converting (+ j-dihydrocodeinone to 1,7 -dibromodihydrocodeinone dimethyl ketal.

11. A process for the production of (+ )-morphine (formula 6) from (- )-sinomenine (formula 1) comprising at least two reaction steps and at least one intermediate product, the at least one intermediate product comprising 1,7- dibromodihydrocodeinone dimethyl ketal (formula 4).

12. A process according to claim 11 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products comprising 7(S)-( + )-dihydrosinomenine or 7(R)-( + )-dihydrosinomenine or a mixture thereof.

13. A process according to claim 11 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products comprising (+ )-dihydrocodeinone.

14. A process according to claim 11 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products comprising (+ j-l-bromocodeinone,

15. A process according to anyone of claims 11 to 14 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products being selected from 7(S)I(R)-(+)-dihydrosinomenine, (+)-dihydrocodeinone and (+ j-l-bromocodeinone.

16. A process according to claim 11 comprising at least four reaction steps providing at least three intermediate products, two of the at least three intermediate products being

(

- 18-

selected from 7(S)/(R)-(+)-dihydrosinomenine, (+)-dihydrocodeinone and (+)-1- bromocodeinone.

17. A process according to claim 16 comprising at least five reaction steps providing at least four intermediate products, three of the at least four intermediate products being 7(S)/(R)-( + )-dihydrosinomenine, (+ )-dihydrocodeinone and (+ )-l-bromocodeinone.

18. A process according to anyone of claims 11 to 17 in which (- j-sinomenine is converted to (+ )-morphine according to the following reaction scheme:

(4) (3)
MeO
Br
1 Step 4
MeO HO (

OMe

- 19 -

Step 1

(2)

OMe

Step 3

Step 5

, - - .

-NMe

(5)

(6)

(

- 20-

19.

A process according to anyone of claims 11 to 18 comprising contacting (-)sinomenine with H2IPdlC under conditions effective for converting (-)sinomenine to 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof; contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)dihydrosinomenine or a mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-( + )-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+)-dihydrocodeinone; contacting the resulting (+)-dihydrocodeinone with (MeO)3CH followed by TsOH followed by NBAIMeOH under conditions effective for converting (+)dihydrocodeinone to 1,7-dibromodihydrocodeinone dimethylketal; contacting the resulting 1,7-dibromodihydrocodeinone dimethylketal with t-butoxide followed by acid under conditions effective for converting 1,7 -dibromodihydrocodeinone dimethylketal to (+ )-l-bromocodeinone; contacting the resulting (+)-1- bromocodeinone with LiAI~ followed by BBr3 under conditions effective for converting (+ )-l-bromocodeinone to (+ )-morphine; and recovering the resulting (+ )-morphine as product.

~, .

I R ,\

r', \ J

:>_..<.:

INVESTOI{ IN PEOPLE

Application No:

Claims searched:

GB 0220385.9 1-19

Examiner:

Date of search:

Peter Davey 9 July 2003

Patents Act 1977 : Search Report under Section 17

Documents considered to be relevant:

Category Relevant Identity of document and passage or figure of particular relevance
to claims
X 1 at least US 4025520 (MACFARLAN SMITH), see ego Exs. 3-5 and
11 Categories.

& Member of the same patent family

E Patent document published on or after, but With priority date earlier than. the filing date of this apphcation

X Document indicating lack of novelty or inventive step

A Document indrcating technological background and/or state of the art

Y Document mdicatmg lack of Inventive step If combined With one or more other documents of same category

P Document published on or after the declared pnonty date but before the tiling date of this Invention

Field of Search:

Search ofGB, EP, WO & US patent documents classified in the following areas of the UKCv.

Worldwide search of alent documents classified in the followin areas of the IPC7,

I WPI, EPODOC, JAPIO, CAS ONLINE

The followjD~ online and other databases have been used !Q the preparatloD of this search report·

An Executive Agency of the Department of Trade and Industry